Project Summary Rosacea is a common skin disorder with an unknown etiology which causes facial redness and inflammation, substantially decreases quality of life, and can cause permanent facial disfigurement. Neuronal dysregulation may play a role in rosacea pathogenesis, because many events that trigger rosacea symptoms are also stressors that are known to increase sympathetic nervous system activity. Our pilot data suggest that individuals with rosacea have increased sympathetic responses to sympathetic stressors. Thus, the proposed project will comprehensively examine the role of sympathetic and sympathetic-like reflexes in rosacea. An increase in sympathetic outflow to the erythema- and flushing-prone areas of the face could be the initiation of the inflammatory etiology of the disease. This research investigates the central hypothesis that neural changes in persons with rosacea precede and drive the inflammatory responses that characterize the disease via three Aims. Specific Aim 1 will determine whether altered sympathetic signals in rosacea are systemic/global vs. local/focal in nature. Specific Aim 2 will indicate which sympathetic receptor population is involved in these rosacea-related changes. Specific Aim 3 seeks to rule out sympathetic-like axon reflex responses, which taken together with expected findings in Aims 1 and 2 would indicate that neural changes in rosacea are the result of the sympathetic nervous system rather than from a local reflex nerve which can mimic the sympathetic responses. Our expertise in the gold-standard direct measurement and analysis of sympathetic neural activity via microneurography, functional receptor identification, and the integrative analysis of cutaneous end-organ responses in this in vivo human model uniquely positions us to investigate the Aims outlined above. Our previous work was the first study to directly quantify sympathetic nerve activity in the facial skin of individuals with rosacea, and we are unaware of any other active labs with the demonstrated expertise and ability to perform these measures. Additional pilot data coupled with the available equipment, facilities, support, and expertise demonstrate that the proposed Specific Aims are achievable and attainable. This project will also allow us to provide undergraduate and graduate students from our institution an opportunity to be fully exposed to and engage in biomedical research and prepare them for future biomedical scientific endeavors. The primary rationale for this project is that these data will provide functional and mechanistic insight into facial flushing in rosacea and have a significant impact on human wellbeing and quality of life. This research is especially significant as a driver of an alternate paradigm for rosacea treatment, with the potential of sympathetic interventions or sympathetic medications being used as a first line of disease-modifying therapy.